Lecture 4: PBC and PSC

Question 1

The three main categories of autoimmune liver disease

Answer 1

autoimmune hepatitis (AIH)
primary biliary cirrhosis (PBC)
primary sclerosing cholangitis (PSC)

Question 2

Primary biliary cholangitits (PBC) General information

Answer 2

Chronic condition in which inflammation causes scarring of both intrahepatic bile ducts

Chronic inflammation in the liver can lead to bile duct damage, irreversible scarring of liver tissue (cirrhosis) and eventually, liver failure.

affects both sexes although mostly affects women
a combination of genetic and environmental factors
there’s no cure for primary biliary cholangitis, but medication can slow liver damage

Question 3

Define PBC

Answer 3

Cholangitis isan inflammation of the bile duct system

Question 4

Early and Late symptoms of PBC

Answer 4

Common early symptoms include:
Fatigue
Itchy skin

Later signs and symptoms may include:
Dry eyes and mouth
Pain in the upper right abdomen
splenomegaly
Bone, muscle or joint (musculoskeletal) pain
Swollen feet and ankles (edema)
ascites
Fatty deposits (xanthomas) on the skin around the eyes, eyelids or in the creases of the palms, soles, elbows or knees
jaundice
Darkening of the skin that’s not related to sun exposure (hyperpigmentation)
osteoporosis
High cholesterol
Diarrhea, which may include greasy stools (steatorrhea)
hypothyroidism
Weight loss

Question 5

Risk factors for PBC

Answer 5

Sex.Most people with primary biliary cholangitis are women.

Age.It’s most likely to occur in people 30 to 60 years old.

Genetics.You’re more likely to get the condition if you have a family member who has or had it.

Geography.It’s most common in people of northern European descent, but primary biliary cholangitis affects all races.
Researchers think that genetic factors combined with certain environmental factors trigger primary biliary cholangitis. These environmental factors may include:

Infections,such as a urinary tract infection

Smoking

Toxic chemicals

Question 6

Overview of role of bile and how this is impacted by PBC

Answer 6

The bile ducts carry bile away from your liver to your small instestine. It aids with digestion and helps you absorb certain vitamins. It also helps your body get rid of cholesterol, toxins and worn-out red blood cells.

When the bile ducts become damaged, they become narrower and harder (fibrosis) reducing the amount of bile moving into the intestines. Over the long term or chronic obstruction of bile, will eventually cause a backpressure of bile into the liver which then induces inflammation (hepatitis).

This inflammation will eventually lead to further fibrosis of the liver tissue and thus cirrhosis

Question 7

PBC pathogenesis diagram and explanation (particulary the start)

Answer 7

Reduced immune tolerance causes the targeting of small interlobular bile ducts causing choleostasis and chronic inflammation and thus cirrhosis. In primary biliary cholangitis, T cells mistakenly destroy the healthy cells lining the small bile ducts in the liver (reduced tolerance).
Inflammation in the smallest ducts spreads and eventually damages other cells in the liver. As the cells die, they’re replaced by scar tissue (fibrosis) that can lead to cirrhosis. Cirrhosis is scarring of liver tissue that makes it difficult for your liver to work properly.

Thus the primary disease mechanism in PBC is thought to be T cell lymphocyte–mediated injury against intralobular biliary epithelial cells. This causes progressive destruction and eventual disappearance of the intralobular bile ducts. A breakdown in tolerance has been suspected as one of the driving causes.

Molecular mimicry has been proposed as the initiating event in the loss of tolerance primarily to mitochondrial pyruvate dehydrogenase complex, E2, during which exogenous antigens evoke an immune response that recognizes an endogenous (self) antigen inciting an autoimmune reaction

Diagram in lecture slide

Question 8

Primary sclerosing cholangitis (PSC)

affects …
symptoms
relation to AID

Answer 8

A rarecondition that affects both the intrahepatic and extrahepatic structures.

Symptoms may includethe following
fatigue and abdomen pain in the first instance, but this can progress to itching, jaundice
Chronic right upper right quadrant pain

The majority ofPSC sufferers also suffer from irritable bowel syndrome (IBS) specifically ulcerative colitis

Question 9

PSC general overview

Answer 9

PSC: chronic, progressive condition characterised by inflammation and scarring of intrahepatic and extra-hepatic bile ducts leading to hardening and strictures (narrowing) of bile ducts causing an obstruction of bile flow. This occurs along the bile duct, affecting some regions and leaving some unaffeced creating the hallmark feature of bead appearance.

Bile ducts carry the bile from the liver to the intestine however, the strictures (narrowing) and fibrosis (hardening) causes obstruction of thebile flow. The impaired bile flow causes backpressure of bile back into the liver with the bile components whihc irritate the liver causing hepatis then fibrosis and finally liver cirrhosis. In PSC, the biliary tree becomes inflamed and damaged overtime stopping the normal flow of bilethrough the liver and to the digestive tract. Thisleads to fibrosis of the biliary ductsand alsoof the liver itself similar to PBC


As inflammation in the intra and extra hepatic ducts progress, cholangiocyte cells that line the bile ducts die which then leads to fibrosis. This fibrosis will create strictures and will then produce what is often referred to as “bead appearance”

Question 10

Cause of PSC

Answer 10

1. strong links to ulcerative colitis (an autoimmune disease) thus PSC is most likely an AID

Thought to be T cells attacking the bile duct epithelial tissue causing hardening and narowing (strictures) of ducts

Question 11

Autoimmune liver serology: Diagnosis based on..

Answer 11

1. histological abnormalities
2. characteristic clinical findings
3. laboratory findings

• elevated serum aspartate aminotransferase [AST]
• elevated alanine aminotransferase [ALT] levels
• increased serum IgG concentration
• the presence of one or more characteristic autoantibodies.

Question 12

Compare PBC and PSC

Female: Male ratio 
Predominant liver test elevation 
Serum Ig elevation
Autoantibodies
HLA -association
Histology 
Diagnosis features 
Medical therapy option

Answer 12

PBC
9:1
Alk Phos, y-GT
IgM
AMA, AMA-M2
DR8
Florid bile duct destruction
AMA, choleostatic liver enzyme pattern
Ursodeoxycholic acid 

PSC
1:2
Alk Phos, y-GT
IgG, IgM
pANCA
DR52
Fibrosis and destruction og large bile ducts 
Biliary strictures, choleostatic liver enzyme pattern, IBD, pANCA
Ursodeoxycholic acid

Question 13

Autoimmune hepatitis

Female: Male ratio 
Predominant liver test elevation 
Serum Ig elevation
Autoantibodies
HLA -association
Histology 
Diagnosis features 
Medical therapy option

Answer 13

4:1
AST, ALT
IgG
ANA, pANCA, ASMA
A3, DR3, DR4
prominent plasma cells, lobualr hepatitis
AIH score above 15
immunosuppression (corticosteroids)

Question 14

Kidney disease:

Answer 14

Goodpasture Syndrome

Not limited to the kidneys but can affect the lungs

Question 15

Goodpasture syndrome information

Answer 15

known as anti-GBM disease

rare autoimmune disease

antibodies attack the basement membrane in lungs and kidneys

can affect just the kidneys (anti-GBM glomerulonephritis) or both the lungs and kidneys

cause bleeding from the lungs, glomerulonephritis
(inflammation of tiny fibres in the kidney), and kidney failure

most commonly affects young, white men (aged 15-35)

Question 16

Anti-GBM Pathogenesis

Answer 16

In anti-GBM disease, the body creates autoantibodies that recognize and attach to the basement membrane, which is part of the wall of capillary blood vessels in the kidneys and lungs. Once the autoantibodies attach to the basement membrane, this creates a signal to the body’s immune system to attack. This causes inflammation and damages the wall causing it to break and spill the contents of the capillary into large empty spaces.

In the kidneys, the autoantibodies damage capillaries (tiny blood vessels) within in theglomeruli.

Question 17

Anti-GBM Pathogenesis specifically in kidney and in lungs

Answer 17

In the kidneys;
the autoantibodies damage capillaries (tiny blood vessels) within in theglomeruli.
The glomeruli are the filters of the kidneys, which filter blood and make urine
Normally when blood goes through the capillaries in the glomeruli, water, electrolytes, and other substances are filtered from the blood into the urine, but larger things like blood cells and proteins are too big to pass through, so stay in the blood and do not pass through the filter into the urine.
However, in anti-GBM disease, the glomeruli (filters) are damaged by the white blood cells and inflammation, and so protein and blood can pass into the urine.
When the autoantibodies attach to the basement membrane in the glomerular capillaries, the inflammation and damage caused by the immune system can occur very quickly and causes the kidney function to decrease.

In the lungs
the capillaries (blood vessels) that are attacked and damaged by the immune system are located in the thin walls of the air sacs where oxygen enters the blood and carbon dioxide exits.
Injury to these pulmonary (lung) capillaries causes bleeding into these air sacs. 
When blood gets into these air sacs it can make it hard to breathe. Specifically, it can cause shortness of breath and low oxygen levels. People may cough up blood as well.

Question 18

PBC
Define

Answer 18

PBC is where t-cells attack the cells (cholangicytes) that line the smaller bile ducts cells in the liver. As the cells are destroyed, bile is able to escape through the leaky junctions and into the interstitial space where it can get into the blood and other liver cells. This results in inflammation and symptoms which are similair to that of choleostasis (jaundice, itchy skin, jaundice, abdominal pain).

At first there is inflammation then cirrhosis due to autoimmune attack and presence of backflow of bile.

Question 19

Cause of PBC and WHY are bile ducts targted

Answer 19

Genetic predisposition and environmental triggers

Antibodies are made to target mitochondria, specifically the PDC-E2 protein (pyruvate dehydrogenase complex) on mitochondria. Therefore, the most known markers for PBC is the presence of anti-mitochondrial antibodies (AMA).

Why are bile duct cells targted though, when all cells have mitochondria and therefore the presence of the PDC-E2 prtotein?
- MOLECULAR MIMICRY PRINCIPLE
Bile duct cells present an antigen which is SIMILAR to another protein (PDC-E2) but it is different enough for the immune system to recognise it as foreign cuasing the immune sysrtem to target it.

For example,
Person A:
Green triangles (antigens) and so lacks the green antibody but will have red, yellow and blue Ab’s. Green is self, so not attacked

Person B
Red triangles (antigens) and so has NO red antibodies, only yellow, green and blue. Red is self, so not attacked.

IF a red triangle turnt GREEN, the immune system would not see this as self antigen. As while the antigen is STILL A TRIANGLE it is different enough (GREEN instead of red) to be recongised as foreign as and induce the production of GREEN antibodies.

SO applying this to PBC, you have these AMA’s for foreign PDC-E2 in mitochondria. So, the body lacks the antibodies to this protein because it seen as SELF (ie red triangle). BUT, when there is an environmental trigger (infection or chemical in the bile ducts) occurs this damages bile duct cells in such a way that the bile duct cell shows this protein that happens to be really similiar to PDC-E2 in strucutre (ie a triangle) BUT its different enough to be NON-SELF (green triangle). This creates an immune response to the altered PDC-E2 protein ONLY by creating massive amounts of AMA’s targeting this altered protein located on bile duct cells. This is why not all cells are targeted as the protein on the bile duct cell isnt actually a mitocondrial protein, justm micmicking the same strcuture causing the AMA formation.

Question 20

Complications of PBC

Answer 20

Complications arise due to bile leakage and liver inflammation
1. Jaundice: Due to bile duct destruction causing bilirubin to leak and conjugated bilirubin to deposit in the skin
2. Xanthmoas: cholestrol
3. Itchy skin: Bile salts in skin
4.Joint pain and arhtropathy

Question 21

Why is ALP and GGT increased in PBC

Answer 21

ALP and GGT stored in the bile duct cells, so when destroyed and die the ALP and GGT are released into the bloodstream.

Question 22

Flow of Bile process

Answer 22

Bile is produced by the hepatocytes and travels through the intra and extrahepatic biliary ducts into the intestine to help digest and absorb fats (including fat soluable vitamins).

Question 23

PBC/PSC general flow

Answer 23

Bile flow obstruction = bile to build up in liver causing chronic inflammation = cirrhosis

Question 24

How is PSC and UC connected?

Answer 24

UC may allow bacteria to leak into the liver’s circulation, which can lead to inflammation

The movement of bacteria from the gut into the portal system generating a systemic inflammatory response which then disrupts the bilairy epithelium leading to exposure of the cholecytes to bile acids and therefore injury. The fibrosis in the bile ducts, decreases the flow of the bile out the liver causing more bile to remain in the liver leading to more chronic inflammation and scarring and thus promoting liver cirrhosis.

Question 25

PSC vs PBC symptoms

Answer 25

PSC:
Fatigue, itchy skin, jaundice, upper abdominal pain, fever, vitamin deficency (fat soluable vitamins), cirrhosis

PBC:
fatigue, itchy skin, jaundice, hyperpigmentation.

Question 26

PBC diagnositic criteria

Answer 26

Elevated ALP (1.5 x the upper limit)
Histological evidence - chronic bilary duct destruction
AMA 1:40 titre or higher

MUST have 2 out of 3 to be diagnosed

Question 27

Some key differences between PBC and PSC
Site of involvement
Autoantibodies
HLA association
Common assosciated conditions
F:M ratio
Treatment purpose
Complications

Answer 27

Site of involvement:
PBC: Intrahepatic bile ducts
PSC: Extrahepatic bile ducts and intrahepatic bile ducts

Autoantibodies:
PBC: AMA, AMA-M2
PSC: P-anca

HLA association
PBC: HLA-DR8
PSC: HLA-DR56

Common assosicated conditons
PBC: Sjogrens
PSC: Ulcerative colitis

Population (F:M)
PBC: 9:1
PSC: 1:2

Treatment purpose
PBC: Ursodeoxycholic acid (improves survival rates)
PSC: Ursodeoxycholic acid (improves LFT’s, not survival outcome)

Complications:
PBC: Cirrhosis
PSC: Colorectal cancer and cirrhosis